This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The insulin degrading enzyme (IDE) is a 110 kDa zinc metallo-endoprotease that degrades several physiologically relevant substrates such as peptide hormones (insulin, glucagon, atrial natriuretic factor, and beta-endophin), amyloid &#946;peptide, and tumor growth factor-alpha. Functional studies have shown that IDE plays important roles in the regulation of developmental and metabolic processes as well as in the development of type 2 diabetes mellitus and Alzheimer?s disease. Thus, IDE is a promising therapeutic target for several human diseases. We have solved the structures of IDE alone and catalytically inactive IDE in complex with several biologically relevant substrates including insulin, amyloid &#946;, glucagon, and bradykinin. Our structures reveal the novel substrate recognition mechanism of this enzyme. One unique feature of IDE is its ability to distinguish the closely related natriuretic peptides. To understand the molecular mechanism for such substrate selectivity, we propose to solve the structures of IDE in complex with natriuretic peptides.